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An abstract of the article "Patterns of Physical Activity in 3-5 Years Old," by A. Blaes, G. Baquet, E. Van Praagh, S. Berthoin, and G. Lensel-Corbeil is presented.

Deals with a study which evaluated a method to quantify the passive stiffness of the ankle by comparing stiffness measurements of normal healthy subjects with those obtained for spastic hemiplegic patients during dorsiflexions imposed at different velocities. Materials and methods used in the study; Results and discussion.

Background: Adrenal tumors are found in up to 40% of patients with multiple endocrine neoplasia type 1 (MEN1). However, adrenocortical carcinomas (ACC) and primary aldosteronism (PA) are rare in MEN1., Case: A 48-year-old woman known to have primary hyperparathyroidism and hypertension with hypokalemia was referred for a right complex 8-cm adrenal mass with a 38.1 SUVmax uptake on 18F-FDG PET/CT. PA was confirmed by saline suppression test (aldosterone 1948 pmol/L-1675 pmol/L; normal range [N]: <165 post saline infusion) and suppressed renin levels (<5 ng/L; N: 5-20). Catecholamines, androgens, 24-hour urinary cortisol, and pituitary panel were normal. A right open adrenalectomy revealed a concomitant 4-cm oncocytic ACC and a 2.3-cm adrenocortical adenoma. Immunohistochemistry showed high expression of aldosterone synthase protein in the adenoma but not in the ACC, supporting excess aldosterone production by the adenoma., Genetic Analysis: After genetic counseling, the patient underwent genetic analysis of leucocyte and tumoral DNA. Sequencing of MEN1 revealed a heterozygous germline pathogenic variant in MEN1 (c.1556delC, p.Pro519Leufs*40). The wild-type MEN1 allele was lost in the tumoral DNA of both the resected adenoma and carcinoma. Sequencing analysis of driver genes in PA revealed a somatic pathogenic variant in exon 2 of the KCNJ5 gene (c.451G>A, p.Gly151Arg) only in the aldosteronoma., Conclusion: To our knowledge, we describe the first case of adrenal collision tumors in a patient carrying a germline pathogenic variant of the MEN1 gene associated with MEN1 loss of heterozygosity in both oncocytic ACC and adenoma and a somatic KCNJ5 pathogenic variant leading to aldosterone-producing adenoma. This case gives new insights on adrenal tumorigenesis in MEN1 patients., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome is caused by aberrant expression of the GIP receptor in adrenal lesions. The bilateral nature of this disease suggests germline genetic predisposition. We aimed to identify the genetic driver event responsible for GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome., Methods: We conducted a multicentre, retrospective, cohort study at endocrine hospitals and university hospitals in France, Canada, Italy, Greece, Belgium, and the Netherlands. We collected blood and adrenal samples from patients who had undergone unilateral or bilateral adrenalectomy for GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome. Adrenal samples from patients with primary bilateral macronodular adrenal hyperplasia who had undergone an adrenalectomy for overt or mild Cushing's syndrome without evidence of food-dependent cortisol production and those with GIP-dependent unilateral adrenocortical adenomas were used as control groups. We performed whole genome, whole exome, and targeted next generation sequencing, and copy number analyses of blood and adrenal DNA from patients with familial or sporadic disease. We performed RNA sequencing on adrenal samples and functional analyses of the identified genetic defect in the human adrenocortical cell line H295R., Findings: 17 patients with GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome were studied. The median age of patients was 43·3 (95% CI 38·8-47·8) years and most patients (15 [88%]) were women. We identified germline heterozygous pathogenic or most likely pathogenic variants in the KDM1A gene in all 17 patients. We also identified a recurrent deletion in the short p arm of chromosome 1 harboring the KDM1A locus in adrenal lesions of these patients. None of the 29 patients in the control groups had KDM1A germline or somatic alterations. Concomitant genetic inactivation of both KDM1A alleles resulted in loss of KDM1A expression in adrenal lesions. Global gene expression analysis showed GIP receptor upregulation with a log2 fold change of 7·99 (95% CI 7·34-8·66; p=4·4 × 10 -125 ), and differential regulation of several other G protein-coupled receptors in GIP-dependent primary bilateral macronodular hyperplasia samples compared with control samples. In vitro pharmacological inhibition and inactivation of KDM1A by CRISPR-Cas9 genome editing resulted in an increase of GIP receptor transcripts and protein in human adrenocortical H295R cells., Interpretation: We propose that GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome results from a two-hit inactivation of KDM1A, consistent with the tumour suppressor gene model of tumorigenesis. Genetic testing and counselling should be offered to these patients and their relatives., Funding: Agence Nationale de la Recherche, Fondation du Grand défi Pierre Lavoie, and the French National Cancer Institute., Competing Interests: Declaration of interests FC, IBo, JB, AL, and PK are registered inventors of a patent for the diagnosis and treatment of endocrine diseases related to KDM1A (#EP21305771·4). All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Recent guidelines on adrenal incidentalomas suggested in patients with an indeterminate adrenal mass and no significant hormone excess that follow up with a repeat noncontrast CT or MRI after 6-12 months may be an option., Methods: We report the case of a 32-year-old woman who presented with a 2.9 × 1.9 cm left adrenal incidentaloma that was stable in size for 4 years. Ten years later the left adrenal mass was a stage IV adrenocortical carcinoma (ACC)., Results: In 2006, a 32-year-old French Canadian woman was referred to endocrinology for a left 2.9 × 1.9 cm incidentally discovered adrenal mass (31 HU). She had normal hormonal investigation. The patient was followed with adrenal imaging and hormonal investigation yearly for 4 years and the lesion stayed stable in size over the 4 years. Ten years later, in 2016, the patient presented with renal colic. Urological CT unexpectedly revealed that the left adrenal mass was now measuring 9 × 8.2 cm and 2 new hepatic lesions were found. Biochemical workup demonstrated hypercorticism and hyperandrogenemia: plasma cortisol after 1 mg overnight DST of 476 nmol/L and DHEA-S of 14.0 μmol/L (N 0.9-6.5). Twenty-four hour urine steroid profiling was consistent with an adrenocortical carcinoma (ACC) co-secreting cortisol, androgens and glucocorticoid precursors. The diagnosis of ACC with hepatic ACC metastases was confirmed at histology. Following genetic analysis, germline heterozygous variant of uncertain significance (VUS) was identified in the exon 16 of the APC gene (c.2414G > A, p.Arg805Gln). Immunohistochemical staining's of the ACC was positive for IGF-2 and cytoplasmic/nuclear β-catenin staining., Conclusions: This case illustrates that (1) small adrenal incidentaloma stable in size may evolve to ACC and (2) better genetic characterization of these patients may eventually give clues on this unusual evolution.

Background: Recently, somatic β-catenin mutations (CTNNB1) identified in aldosterone-producing adenomas (APAs) from three women were suggested to be responsible for the aberrant overexpression of luteinizing hormone/choriogonadotropin receptor and gonadotropin-releasing hormone receptor in the APA., Objective: To genetically characterize patients with primary aldosteronism (PA) evaluated in vivo for gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH)-responsive aldosterone secretion., Method: Patients with PA were evaluated in vivo to determine the possible regulation of aldosterone secretion by GnRH or LH. Genetic analysis of the CTNNB1, KCNJ5, ATP1A1, ATP2B3, CACNA1D, and GNAS genes were performed in this cohort and a control cohort of PA not tested in vivo for GnRH response., Results: We studied 50 patients with confirmed PA, including 36 APAs, 12 bilateral macronodular adrenal hyperplasias, 1 oncocytoma, and 1 bilateral hyperplasia with cosecretion of cortisol. Among 23 patients tested in vivo for GnRH response of aldosterone, 7 (30.4%) had a positive response, 4 (17.4%) a partial response, and 12 (52.2%) no response. No somatic CTNNB1 mutations were identified, but the disease-causing c.451G>C KCNJ5 mutation was found in two individuals with partial and no GnRH responses and an individual showing a positive response to LH. Two additional somatic pathogenic mutations, CACNA1D c.776T>A and ATP1A1 c.311T>G, were identified in two patients with no GnRH responses. In the 26 patients not tested for GnRH response, we identified 2 CTNNB1 (7.7%), 13 KCNJ5 (50%), and 1 CACNA1D (3.8%) mutations., Conclusion: Aberrant regulation of aldosterone by GnRH is frequent in PA, but is not often associated with somatic CTNNB1, although it may be found with somatic KCNJ5 mutations.

Introduction: Thiazolidinediones are increasingly used drugs for the treatment of Type 2 diabetes. The individual response to thiazolidinedione therapy, ranging from the variable degree of metabolic improvement to harmful side-effects, is empirical, yet the underlying mechanisms remain elusive. In order to assess the pharmacogenomic component of thiazolidinediones' metabolic action, we compared the effect of rosiglitazone in two genetically defined models of metabolic syndrome, polydactylous (PD) and BN.SHR4 inbred rat strains, with their insulin-sensitive, normolipidemic counterpart, the Brown Norway (BN) rat., Materials & Methods: 5-month-old male rats were fed a high-fat diet for 4 weeks, and the experimental groups received rosiglitazone (0.4 mg/100 g body weight) during the last 2 weeks of high-fat diet feeding. We assessed metabolic and morphometric profiles, oxidative stress parameters and gene expression in white adipose tissue., Results: In many followed parameters, we observed genetic background-specific effects of rosiglitazone administration. The mass and the sensitivity of visceral adipose tissue to insulin-stimulated lipogenesis increased with rosiglitazone treatment only in PD, correlating with a PD-specific significant increase in expression of prostaglandin D2 synthase. The glucose tolerance was enhanced in all strains, although fasting plasma glucose was increased by rosiglitazone in BN and BN.SHR4. Among the markers of lipid peroxidation, we observed the rosiglitazone-driven increase of plasma-conjugated dienes only in BN.SHR4. The genes with genotype-specific expression change included ADAM metallopeptidase domain 7, aquaporin 9, carnitine palmitoyltransferase 1B, caveolin 1, catechol-O-methyl transferase, leptin and prostaglandin D2 synthase 2., Conclusion: Rosiglitazone's effects on lipid deposition and insulin sensitivity of peripheral tissues are largely dependent on the genetic background it acts upon.

Background: Although numerous studies revealed that isokinetic dynamometers were valuable tools for assessing spastic hypertonia, no standard methodology using such devices is currently widespread in clinical setting. The aim of this study was to standardize a protocol to assess spastic hypertonia in the triceps surae., Methods: The passive resistance during dorsiflexions imposed from 10 to 300 degrees /s with an isokinetic dynamometer was measured at the neutral position in 15 patients with spastic hypertonia and 12 healthy subjects. The normalized passive resistance was obtained by expressing raw passive resistance as a percent of the values measured at the lowest velocity (10 degrees /s). EMG signals from plantar and dorsiflexors were also recorded., Findings: While no significant difference between spastic patients and control subjects was observed in raw passive resistance values, the difference was significant for each tested velocity when considering the normalized values. Furthermore, the Ashworth score was significantly correlated with the normalized passive resistance for each velocity whereas no correlation was observed with the raw passive resistance. For the patients, except at the highest velocity, the normalized passive resistance was not affected by the fact that reflex responses in the triceps surae were elicited or not., Interpretation: The normalized passive resistance, expressed with respect to the initial one, i.e., measured at very low velocity, seems a very effective parameter to quantify the velocity-dependent increase in resistance to passive stretch in spastic plantarflexors. However, while the simplicity of the isokinetic tests and the reduced time of data treatment seems to support the clinical use of this methodology, further investigations are required to definitely standardize the protocol.

Objective: The purpose of this study was first to compare the kinematic parameters of imposed ankle mobilizations measured during Ashworth or isokinetic tests and, second, to better understand why the stretch reflex was more or less easily elicited by one method or the other., Methods: Passive dorsiflexions were applied on eight adult patients with plantarflexor spasticity in two conditions: (i) manually, using the Ashworth test where passive dorsiflexions were performed freely by seven rehabilitation clinicians, and (ii) instrumentally, using an isokinetic device (Cybex Norm) and a dorsiflexion velocity at 300 degrees /s. Mean values of initial ankle position, maximal angular velocity (theta;'(max)), maximal angular acceleration (theta;''(max)) and plantarflexor reflex responses obtained with each method were compared., Results: During the Ashworth test, all the patients presented reflex activities in the triceps surae while, during the isokinetic mobilization, only three out of the eight patients tested shown reflex responses. theta;'(max) values were significantly higher (P<0.05) in the manual test (308+/-80 degrees /s vs 216+/-5.5 degrees /s for the isokinetic test). The most marked difference concerned the theta;''(max) values (5046+/-2181 degrees /s(2) for the Ashworth test vs 819+/-18 degrees /s(2) for the isokinetic test, P<0.001). This parameter was significantly correlated with the mean rms-EMG values of the gastrocnemius lateralis (GL) and the soleus (SOL)., Conclusions: This study indicates that passive dorsiflexions imposed during Ashworth and isokinetic tests largely differ in velocity and acceleration, and the higher dynamic parameters evaluated during the Ashworth test could mainly explain that the stretch reflex was more easily elicited during this manual testing., Significance: If isokinetic devices offer numerous advantages in the assessment of passive resistance to spastic muscle stretch, they cannot be used to simulate the manual test.

We report the specific detection of a few hundred molecules of genetic material using a fluorescent polythiophene biosensor. Such recognition is based on simple electrostatic interactions between a cationic polymeric optical transducer and the negatively charged nucleic acid target and can be done in less than 1 h, simply and affordably, and without any chemical reaction. This simple system is versatile enough to detect nucleic acids of various lengths, including a segment from the RNA genome of the Influenza virus.

This study determined the effects of a short period of knee isometric training on the quadriceps muscles accessible to surface electromyography (EMG). For this purpose, a training (n = 9) and a control (n = 7) group were tested on five identical occasions at 1 week intervals during 4 weeks. The training group exercised three times a week by making isometric knee extensions at 80% of the maximal voluntary contraction (MVC). During the test sessions, maximal and submaximal torque and associated activations of the rectus femoris (RF), vastus lateralis (VL) and vastus medialis (VM) muscles were analysed. As a result of training, differences between MVC values of the two groups were highly significant (P<0.001), whereas only RF-EMG showed significant differences (P<0.05). The VL and VM did not present any significant changes in maximal activation. The EMG torque relationships were analysed individually before and after the training period. For the control subjects, EMG-torque relationships did not present significant changes while for the training group, these relationships showed a significant increase in RF, VL, and VM maximal activation in 6, 6 and 4 subjects, respectively, and a significant decrease in 1, 2 and 5 subjects, respectively. In almost all cases, a significant downward shift of the relationship was observed. This study confirmed that the parts of the quadriceps muscle tested present different adaptation capacities and demonstrate inter-individual variability in the strategies used to enhance muscle strength. In conclusion, to analyse the neural effects resulting from training in a large and compartmentalized muscle like the quadriceps femoris, it is desirable to take into account each muscle independently. Moreover, we suggest that overall results obtained from the experiment population should be completed by an analysis on individuals.

In order to compare the Maximal Aerobic Speed (MAS) evaluated with different methods, eleven male physical education students (22.2 +/- 3.0 years) were submitted to a maximal treadmill protocol and to the Université de Montréal Track Test (UMTT). Four methods were used to calculate MAS. After treadmill measurement of VO2max, MAS was calculated (MAS&#95;calc) by the following formula: MAS&#95;calc = (VO2max - 0.083)/C, where VO2max is the maximal oxygen uptake (ml.kg-1.s-1) and C the energy cost of running (ml.kg-1.m-1). The extrapolated MAS (MAS&#95;ex) was obtained from the measured VO2max and by extrapolation of the VO2 versus speed relationship. The MAS for treadmill measurement (MAS&#95;tr) and for UMTT (MAS&#95;UMTT) were the velocities at the last completed stages. The average MAS&#95;calc (4.71 +/- 0.48 m.s-1), MAS&#95;ex (4.62 +/- 0.48 m.s-1), MAS-tr (4.75 +/- 0.57 m.s-1) and MAS&#95;UMTT (4.64 +/- 0.35 m.s-1) were not significantly different and were significantly correlated, between 0.85 (MAS&#95;ex vs MAS&#95;UMTT) and 0.99 (MAS&#95;calc vs MAS&#95;tr), with p < 0.001 in both cases. MAS measurements were significantly correlated to measured VO2max but independent of C.

The aims of this study were to use the Maximal Aerobic Speed (MAS) to set training intensities for aerobic training and to measure the effects of two different training programmes on MAS and on the running time to exhaustion at 100% of MAS (Tlim) for 121 students aged 14 to 17 years. The MAS was measured using the Université de Montréal Track Test (UMTT). This measurement was found reproducible for males (r = 0.93) and females (r = 0.68). The Students followed a 12-week training programme of one weekly training session. The MAS and the Tlim were measured the weeks before and after training. Two training programmes were proposed (intense training programme and moderate training programme). These training programmes differed by the ratio between continuous exercises (85% of MAS) and intermittent exercise (between 90% and 120% of MAS). For the moderate training programme, the ratio between continuous and intermittent exercises was greater than for the intensive training programme. Twenty subjects served as control group. The students MAS and Tlim (mean +/- SD) were respectively 13.7 +/- 1.6 km.h-1 and 380.5 +/- 91.8 s for the males and 11.3 +/- 1.2 km.h-1 and 347.2 +/- 91.1 s for the females. Our results indicated that only the subjects of the intense training group improved their MAS: + 5.7% for the males (p < 0.001) and + 5.4% for the females (p < 0.001). In neither case was Tlim significantly improved with training. In conclusion, we can notice that MAS is a pertinent criterion to set training intensities for aerobic training and that a weekly training session over 12 weeks is sufficient to moderately improve the MAS of initially untrained students.